Potent and selective agonism of the melanocortin receptor 4 with mk-0493 does not induce weight loss in obese human subjects: Energy intake predicts lack of weight loss efficacy

R. Krishna, B. Gumbiner, C. Stevens, B. Musser, M. Mallick, S. Suryawanshi, L. Maganti, H. Zhu, T. H. Han, L. Scherer, B. Simpson, D. Cosgrove, K. Gottesdiener, J. Amatruda, B. J. Rolls, J. Blundell, G. A. Bray, K. Fujioka, S. B. Heymsfield, J. A. WagnerG. A. Herman

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.

Original languageEnglish (US)
Pages (from-to)659-666
Number of pages8
JournalClinical pharmacology and therapeutics
Volume86
Issue number6
DOIs
StatePublished - 2009

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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